2-(2-Chloro-4-cyclopropyl-phenyl-imino)-imidazolidine, and acid addition salts thereof as bradycardiacs

ABSTRACT

This invention is directed to 2-(2-chloro-4-cyclopropyl-phenyl-imino)-imidazolidine, and acid addition salts thereof, the preparation of said compounds, and the use of said compounds as bradycardiacs.

The present invention relates to2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine of the formula:##STR1## and the physiologically acceptable acid addition salts thereof,having valuable therapeutical properties.

The compound of formula I and the acid addition salts thereof may beprepared by one of the following processes (a) to (c):

(a) reacting a compound of the formula: ##STR2## (wherein A represents acyano group or the radical ##STR3## in which Y represents an alkoxy oralkylthio group having 1 to 4 carbon atoms or a sulfhydryl or aminogroup) with ethylene diamine or an acid addition salt thereof.

The reaction is effected at a temperature of from 100° to 250° C. Polarprotic, polar aprotic or non-polar solvents may be used as solvent. Thereaction may, however be effected without the use of a solvent in whichcase the reaction is effected at an elevated temperature. The reactiontime varies from a few minutes to several hours.

(b) reaction of a compound of the formula: ##STR4## (wherein X and Z,which may be the same or different, each represent a halogen atom or analkoxy or alkylthio group with 1 to 4 carbon atoms) with ethylenediamine or an acid addition salt thereof. If X and Z represent a halogenatom, preferably a chlorine atom, the reaction is effected at atemperature of from 0° C. to ambient temperature. Inert solvents such asfor example ethers, ketones, esters or aliphatic or aromatichydrocarbons may be used as solvent.

If X and Z represent alkoxy or alkylthio group, the reaction is effectedat an elevated temperature, preferably at the reflux temperature of thereaction mixture. Polar protic, polar aprotic or non-polar solvents maybe used as solvent.

(c) deacylation of a compound of the formula: ##STR5## (wherein Acylrepresents an aliphatic or aromatic acyl group) by reaction with analiphatic alcohol or a dilute mineral acid.

Compounds of formula II may be obtained reacting2-chloro-4-cyclopropylaniline with a cyanate or thiocyanate, a urea orthiourea being formed. The urea or thiourea may then be converted intothe corresponding isouronium salt or isothiouronium salt for example, bythe use of an alkylating agent. The corresponding isourea or isothioureamay be obtained from these acid addition compounds with bases. Bydehydration of the urea or by removal of H₂ S from the thiourea in thepresence of lead or mercury salts 2-chloro-4-cyclopropyl-phenylcyanamideis obtained, with which ammonia may be reacted to form2-chloro-4-cyclopropyl-phenyl-guanidine.

The isocyanide dichloride of formula III may be obtained by reaction of2-chloro-4-cyclopropylaniline with formic acid followed by reaction ofthe formanilide obtained with a mixture of thionyl chloride andsulphuryl chloride.

Other starting compounds of formula III may be obtained by reacting theisocyanide dichloride with an alcohol or thioalcohol.

The starting compounds of formula IV may be prepared by reacting2-chloro-4-cyclopropylaniline with an N-acyl-imidazolidinone-(2) in thepresence of phosphorus oxychloride.

The 2-phenylimino-imidazolidine of the present invention may, ifdesired, be converted into a physiologically compatible acid additionsalt by convertional methods. Acids suitable for salt formation includefor example hydrochloric acid, hydrobromic acid, hydroiodic acid,hydrofluoric acid, sulphuric acid, phosphoric acid, nitric acid, aceticacid, propionic acid, butyric acid, caproic acid, valeric acid, oxalicacid, malonic acid, succinic acid, maleic acid, fumaric acid, lacticacid, tartaric acid, citric acid, malic acid, benzoic acid,p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamicacid, salicyclic acid, ascorbic acid, methanesulphonic acid and8-chlorotheophylline.

The novel compound of formula I and the physiologically compatible acidaddition salts possess a strong bradycardiac activity and are suitablefor the treatment of coronary diseases. The influence of the saidcompound on the heart beat frequency has been investigated in rabbitsand in pithed rats as well as in live anaesthetised rats.

The dosage ranges from 0.1 to 80 mgm, preferably from 1 to 30 mgm.

The compound of formula I as well as the acid addition salts thereof mayalso be combined with other active ingredients. Suitable pharmaceuticalcompositions include e.g. tablets, capsules, suppositories, solutions orpowders. For the preparation of pharmaceutical compositions conventionalexcipients, carriers, disintegrants or lubricants or agents forobtaining sustained release may be used.

The following Examples illustrate the invention without restricting itsscope:

EXAMPLE 1 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine ##STR6##

Molecular weight: 235.7

Molecular formula: C₁₂ H₁₄ CIN₃

Melting point: 133.5°-138.5° C.

    ______________________________________    Elementary analysis:                    C      H        Cl   N    ______________________________________    Calculated      61.15  5.99     15.04                                         17.83    Found           61.07  6.05     15.42                                         17.66    ______________________________________

(a) N-(2-chloro-4-cyclopropyl-phenyl)-S-methyl-isothiouronium iodide

4-Cyclopropylaniline is acetylated to 4-cyclopropyl-acetanilide (m.p.111°-113.5° C.) and is chlorinated and saponified to2-chloro-4-cyclopropylaniline as described in J. Amer. Chem. Soc. 62(1940), 2103. The title compound is obtained by reaction of the anilinewith ammonium thiocyanate followed by methylation of the resultingN-(2-chloro-4-cyclopropyl-phenyl)-thiourea with methyl iodide.

(b) 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine

8.30 g of N-(2-chloro-4-cyclopropyl-phenyl)-S-methyl-isothiouroniumiodide are refluxed for 15 hours in 25 ml of methanol together with 2.3ml (150%) of ethylene diamine. The clear reaction mixture is thenevaporated in vacuo and a honey-like residue is left. This is dissolvedin 1 N HCl and the hydrochloric acid solution is extracted twice withether. The aqueous phase is subsequently buffered to pH 6 with 2 N NaOHand extracted with ether (50-ml portions) in fractions with rising pHvalues (fractioned alkalisation with 2 N NaOH). The approximatelyuniform ether fractions are combined (by a thin-layer chromatogramcheck), dried over MgSO₄ and evaporated in vacuo. For furtherpurification the crude2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine is chromatographedover silica gel.

Eluant: isopropanol:ethyl acetate:concentrated ammonia=50:50:1. Yield:1.3 g (corresponding to 23.6% of theory).

Melting point: 135.5° to 138.5° C.

Thin-layer chromatogram

System: isopropanol:ethyl acetate:concentrated ammonia (50:50:1).

Carrier: silical gel plates by Merck-Darmstadt No. 60F254.

Detector: (a) UV, (b) potassium iodoplatinate according to Schlittler.

Rf: 0.3.

PHARMACEUTICAL COMPOSITION EXAMPLES Example A: Coated tablets

    ______________________________________    Active substance according to invention                                   5 mg    Lactose                        65 mg    Corn starch                    130 mg    Secondary calcium phosphate    40 mg    Soluble starch                 3 mg    Magnesium stearate             3 mg    Colloidal silicic acid         4 mg                           Total   250 mg    ______________________________________

Preparation

The active substance is mixed with a part of the excipients, kneadedintensively with an aqueous solution of the soluble starch andgranulated in conventional manner by means of a sieve. The granulate ismixed with the rest of the excipients and pressed into coated tabletcores weighing 250 mg which are then coated in a conventional mannerwith a coating of sugar, talcum and gum arabic.

Example B: Ampoules

    ______________________________________    Active substance according to the invention                              1.0    mg    Sodium chloride           18.0   mg    Distilled water sufficient to make                              2.0    ml    ______________________________________

Preparation

The active substance and sodium chloride are dissolved in water andfilled, under nitrogen, into glass ampoules.

Example C: Drops

    ______________________________________    Active substance according to the invention                               0.02 g    Methyl-p-hydroxybenzoate   0.07 g    Methyl-p-hydroxybenzoate   0.03 g    Demineralised water sufficient to make                               100 ml    ______________________________________

What we claim is:
 1. A compound of the formula ##STR7## or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 2. Abradycardiac pharmaceutical composition consisting essentially of aninert pharmaceutical carrier and an effective bradycardiac amount of acompound of claim
 1. 3. A method for slowing the heart rate of awarm-blooded animal in need thereof, which comprises orally, parentally,or rectally administering an effective bradycardiac amount of a compoundof claim 1.